Estrogens regulate a variety of physiological processes in mammals, including reproduction, bone integrity, cellular homeostasis, and cardiovascular and central nervous systems. Estrogen (17β-estradiol, E2) belongs to a family of steroid hormones that act through soluble intracellular receptors by binding to high-affinity receptors on target cells. Upon activation by estrogens, these receptors translocate to the nucleus, where they function as ligand-dependent transcription factors. Aside from a few notable exceptions, estrogenic ligands exhibit similar affinities for the two receptor subtypes ERα and ERβ.
The canonical therapy for ER-positive breast cancers employs the partial antiestrogen tamoxifen. Tamoxifen has clearly demonstrated improved prognosis in disease recurrence and overall survival in the management of early-stage breast cancer. Furthermore, recent clinical studies suggest that tamoxifen can be used prophylactically as a chemopreventive agent for hormone-dependent breast cancer.
However, drawbacks emanating from long-term treatment with tamoxifen include acquired clinical resistance and an increased risk for endometrial cancer and related uterotropic effects. Recognition of these factors has stimulated the active pursuit of alternative selective ER modulators (SERMs) that exert differential agonist and antagonistic effects in various estrogen target tissues. Raloxifene, another SERM in clinical use, was developed to improve the drug safety profile by avoiding some of the undesirable estrogen agonist actions of other SERMs.
In view of their enormous medical potential, there is a great need for fast, reliable tools to identify potential SERMs.